Immune Balance Research Articles

The relationship between serum resolvin D1, NLRP3, cytokine levels, and adolescents with first-episode medication-naïve major depressive disorder

BackgroundInflammation has become a critical pathological mechanism of Major Depressive Disorder (MDD). NLRP3 is a critical inflammatory pathway to maintain the immune balance. Recently, preclinical evidence showed that Resolvin D1 might potentially offer a new option for antidepressant treatment due to its protective effects through the inhibition of neuroinflammation. However, whether they have clinical value in the diagnosis and treatment evaluation of adolescent depression was unclear.MethodsForty-eight untreated first-episode adolescent patients with moderate to severe major depressive disorder, as well as 30 healthy adolescents (HCs, age and gender-matched), were enrolled for this study. Their ages ranged from 13 to 18 (15.75 ± 1.36) years. The patients were treated with fluoxetine for 6–8 weeks. HDRS-17 was used to evaluate the severity of depressive symptoms. Venous blood samples were collected at baseline for the two groups and at the time-point of post-antidepressant treatment for the patients. Serum concentrations of RvD1, NLRP3, IL-1β, IL-18, and IL-4 were measured by enzyme-linked immunosorbent assays (ELISA) pre- and post-fluoxetine treatment.ResultsSerum levels of RvD1 and anti-inflammatory cytokine IL-4 were significantly elevated in adolescents with MDD compared to healthy adolescents, but no significant difference in NLRP3, IL-1β, and IL-18 between the two groups. Meanwhile, RvD1 (positively) and IL-4 (negatively) were correlated with the severity of symptoms (HDRS-17 scores) after adjusting age, gender, and BMI. Interestingly, fluoxetine treatment significantly reduced the serum levels of RvD1, NLRP3, IL-1β, and IL-18 in MDD adolescents but increased the levels of IL-4 relative to baseline. Furthermore, we observed that serum levels of RvD1 might be an excellent distinguishing indicator for depression and healthy adolescents.ConclusionsOur study is the first to compare RvD1 and NLRP3 between adolescent MDD and HCs. Our findings of reactive increase of RvD1 in adolescent MDD comprised a novel and critical contribution. Our results showed the presence of inflammation resolution unbalanced in adolescents with MDD and indicated that RvD1 might be an ideal biomarker for diagnosing and treating adolescent MDD.

Succinic Acid Ameliorates Concanavalin A-Induced Hepatitis by Altering the Inflammatory Microenvironment and Expression of BCL-2 Family Proteins.

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment methods. Our study aimed to evaluate the protective effect of succinic acid against AIH and provide a reliable method for the clinical treatment of AIH. We performed an in vivo study of the effects of succinic acid on concanavalin A (ConA)-induced liver injury in mice. We examined liver transaminase levels, performed hematoxylin and eosin (HE) staining, and observed apoptotic phenotypes in mice. We performed flow cytometry to detect changes in the number of neutrophils and monocytes, and used liposomes to eliminate the liver Kupffer cells and evaluate their role. We performed bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting to detect mitochondrial apoptosis-induced changes in proteins from the B-cell lymphoma 2(Bcl-2) family. Succinic acid ameliorated ConA-induced AIH in a concentration-dependent manner, as reflected in the survival curve. HE and TUNEL staining and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed decreased alanine transaminase and aspartate aminotransferase levels, and reduced liver inflammation and apoptosis. RT-qPCR and enzyme-linked immunosorbent assay revealed that succinic acid significantly reduced liver pro-inflammatory cytokine levels. Flow cytometry revealed significantly decreased levels of liver neutrophils. Moreover, the protective effect of succinic acid disappeared after the Kupffer cells were eliminated, confirming their important role in the effect. Bioinformatics analysis, RT-qPCR, and western blotting showed that succinic acid-induced changes in proteins from the Bcl-2 family involved mitochondrial apoptosis, indicating the molecular mechanism underlying the protective effect of succinic acid. Succinic acid ameliorated ConA-induced liver injury by regulating immune balance, inhibiting pro-inflammatory factors, and promoting anti-apoptotic proteins in the liver. This study provides novel insights into the biological functions and therapeutic potential of succinic acid in the treatment of autoimmune liver injury.

Effects of 2,4-dichlorophenol on non–specific immunity, histopathological lesions, and redox balance in African Catfish, clarias gariepinus (Burchell, 1822)

ABSTRACT The toxic effects of 2, 4-dichlorophenol (2, 4-DCP) on aquatic organisms are well-established; however, the details regarding the mechanisms underlying the toxicity, especially immunotoxicity are poorly understood. Consequently, the aim of this study was to investigate the histopathologic, oxidative stress and immunotoxic effects attributed to exposure to sublethal concentrations of 2,4-DCP in the African catfish, Clarias gariepinus. Juvenile C. gariepinus were exposed to 0.4, 0.8, or 1.6 mg/L 2, 4-DCP for 28 days after which blood and head kidney were extracted for the determination of various nonspecific innate immune parameters while the liver was excised for histopathology examination and measurement of oxidative stress biomarkers. Control fish were maintained in water spiked 10 µL/L ethanol, representing the solvent control. A significant increase was noted in the activities of lactate dehydrogenase and superoxide dismutase as well as in levels of lipid peroxidation and DNA fragmentation in a dose-dependent manner, with higher adverse effects observed at the highest concentration tested (1.6 mg/L). The total white blood cells (WBC) count was significantly elevated in fish exposed to 2,4-DCP compared to control. Myeloperoxidase content was decreased significantly in fish exposed to 2,4-DCP especially at the highest concentration (1.6 mg/L) compared to controls. The respiratory burst activity did not differ markedly amongst groups. Histopathological lesions noted included edema, leucocyte infiltration, and depletion of hemopoietic tissue in the head kidney of exposed fish. There was significant upregulation in the mRNA expression of tumor necrosis factor (TNF-α) and heat shock protein 70 (HSP 70) but downregulation of major histocompatibility complex 2 (MHC 2) in exposed fish. Data demonstrated that exposure to 2,4-DCP resulted in histopathological lesions, oxidative stress, and compromised immune system in C. gariepinus.

The endophytic microbiome response patterns of Juglans regia to two pathogenic fungi.

The endophytic microbial community reassembles to participate in plant immune balance when the host plants are stressed by pathogens. However, it remains unclear whether this assembly is pathogen-specific and how regulatory pathways are coordinated in multi-pathogens. In order to investigate the effects of infection with Colletotrichum gloeosporioides (Cg treatment) and Fusarium proliferatum (Fp treatment) on walnut leaf endophytic microbiome in their assembly, co-occurrence pattern, and on comprehensive chemical function of the internal environment of leaf, an interaction system of the walnut-pathogenic fungi was constructed using seed embryo tissue culture technology. The study showed differences in the assembly of endophytic microbial communities in walnut trees across three groups (control group, Ck; Cg; Fp) after Cg and Fp treatments. Despite changes in relative abundances, the dominant communities in phyla and genera remained comparable during the infection of the two pathogens. Endophyte fungi were more sensitive to the pathogen challenge than endophyte bacteria. Both promoted the enrichment of beneficial bacteria such as Bacillus and Pseudomonas, changed the modularity of the community, and reduced the stability and complexity of the endophyte community. Pathogenic fungi infection mainly affects the metabolism of porphyrin and chlorophyll, purine metabolism, phenylpropane metabolism, and amino acid metabolism. However, there was no significant difference in the secondary metabolites for the different susceptible plants. By screening endogenous antagonistic bacteria, we further verified that Pseudomonas psychrotolerans and Bacillus subtilis had inhibitory effects on the two pathogenic fungi and participated in the interaction between the leaves and pathogenic fungi. The antibacterial substances may be 1-methylnaphthalene, 1,3-butadiene, 2,3-butanediol, and toluene aldehyde.

Heat/non-heat treatment alleviates β-conglycinin-triggered food allergy reactions by modulating the Th1/Th2 immune balance in a BALB/c mouse model.

With the increasing popularity of plant protein-based diets, soy proteins are favored as the most important source of plant protein worldwide. However, potential food allergy risks limit their use in the food industry. This work aims to reveal the mechanism of β-conglycinin-induced food allergy, and to explore the regulatory mechanism of heat treatment and high hydrostatic pressure (HHP) treatment in a BALB/c mouse model. Our results showed that oral administration of β-conglycinin induced severe allergic symptoms in BALB/c mice, but these symptoms were effectively alleviated through heat treatment and HHP treatment. Moreover, β-conglycinin stimulated lymphocyte proliferation and differentiation; a large number of cytokines interleukin (IL)-4, IL-5, IL-10, IL-12 and IL-13 were released and interferon γ secretion was inhibited, which disrupted the Th1/Th2 immune balance and promoted the differentiation and proliferation of naive T cells into Th2-type cells. Heat/non-heat treatment altered the conformation of soybean protein, which significantly reduced allergic reactions in mice. This regulatory mechanism may be associated with Th1/Th2 immune balance. Our results provide data support for understanding the changes in allergenicity of soybean protein within the food industry. © 2024 Society of Chemical Industry.

Genome-wide identification and expression analysis of the Nitrile-specifier proteins (NSPs) in Brassica napus

The complete exploitation of Brassica napus plants is a study hotspot, since it is an essential oil crop that is widely cultivated across the world. Glucosinolate is a unique secondary metabolite in the Brassicaceae family, and its content has a substantial influence on rapeseed development and quality. Its degradation products have various physiological functions, among which Nitrile specific proteins (NSPs) can hydrolyze glucosinolate and hence influence the balance of plant immunity and growth. However, the related gene families in B. napus have not been investigated. Here, 72 NSP family members were discovered and described in B. napus based on their sequence structures, physiological correlations, phonological locations, and expression levels. According to collinearity studies, the NSP proteins in B. napus and A. thaliana are closely related. Analysis of BnNSP expression patterns in various tissues revealed that BnNSPs exhibit high tissue specificity, implying that BnNSPs may play distinguish functions in various developmental phases. We discovered that NSPs may be regulated by hormones such as abscisic acid (ABA), gibberellin (GA), and metallic jasmonate (MeJA) based on the expression of NSPs during hormone treatment. The results provide valuable information for the future functional characterization of BnNSP genes.

Characterization of the potential allergenicity of enzymatically hydrolyzed casein in Balb/c mouse model.

Bovine casein is a major allergen present in cow milk to induce anaphylaxis. In this study, the potential allergenicity of enzymatically hydrolyzed casein (HC) was evaluated based on in vitro and in vivo. The results showed that Alcalase and Protamex treatment (AT, PT) reduced the potential allergenicity of CN, with the greatest reductions of 68.25% and 50.75%, respectively. In addition, in vivo results showed that HC effectively alleviated allergic response symptoms of Balb/c mice; a significant tendency toward decreased serum IgG1 and mast cell tryptase levels was observed, accompanied by a decrease of Th2-associated IL-4, IL-5, and IL-13 and an increase of IFN-γ levels in spleen. Moreover, the inflammation of the lung, jejunum, and ileum was remarkably ameliorated. The findings indicated that HC induced a shift toward Th1 response and maintained the Th1/Th2 immune balance. Importantly, our results provide the basis for the production of hypoallergenic dairy products.

Recent Advances in Immunomodulatory Therapy in Sepsis: A Comprehensive Review.

Sepsis remains a critical healthcare challenge, characterized by dysregulated immune responses to infection, leading to organ dysfunction and high mortality rates. Traditional treatment strategies often fail to address the underlying immune dysregulation, necessitating exploring novel therapeutic approaches. Immunomodulatory therapy holds promise in sepsis management by restoring immune balance and mitigating excessive inflammation. This comprehensive review examines the pathophysiology of sepsis, current challenges in treatment, and recent advancements in immunomodulatory agents, including biologics, immunotherapy, and cellular therapies. Clinical trial outcomes, safety profiles, and future research and clinical practice implications are discussed. While immunomodulatory therapies show considerable potential in improving sepsis outcomes, their successful implementation requires further research, collaboration, and integration into standard clinical protocols.

Type I/II Immune Balance Contributes to the Protective Effect of AIF-1 on Hepatic Immunopathology Induced by Schistosoma japonicum in a Transgenic Mouse Model.

Schistosomiasis is the second most debilitating neglected tropical disease in the world. Liver egg granuloma and fibrosis are the main damage of schistosomiasis. In this study, the role of allograft inflammatory factor-1 (AIF-1) in liver pathology and its regulation in immune responses were investigated in a transgenic mouse infected with Schistosoma japonicum. We found that AIF-1 overexpression reduced worm burden and decreased egg granuloma sizes and serum alanine aminotransferase levels, along with inhibited hepatic collagen deposition and serum hydroxyproline levels during S. japonicum infection. Moreover, AIF-1 overexpression resulted in an increased ratio of Th1/Th2, increased levels of IFN-γ and T-bet, and lower levels of GATA-3 in the spleen, accompanied by increased M1 percentages, decreased M2 percentages, and thus a higher ratio of M1/M2 in the peritoneal cavity and liver. AIF-1 induced CD68 and iNOS mRNA expression and protein levels of cytoplasmic p-P38 and nuclear NF-κB, along with enhanced levels of TNF-α and TGF-β in macrophages in vitro. Moreover, the hepatic pathology had a negative correlation with Th1/Th2 and M1/M2 ratios in the infected mice. The findings reveal that the beneficial role of AIF-1 in alleviating hepatic damage is related to restoring type I/II immune balance in S. japonicum infection.

Immune cell balance as potential biomarker of progressing non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a widespread chronic, slowly progressive metabolic multifactorial disease. It is represented by several clinical and morphological forms: steatosis, nonalcoholic steatohepatitis (NASH) (with or without fibrosis), and liver cirrhosis. The search for minimally invasive and cost-effective biomarkers of NAFLD is a key task in the diagnosis, staging of progression, and long-term monitoring of NAFLD. This article discusses the possibility of using immune cell balance as potential minimally invasive peripheral markers of NAFLD progression. In the progression of NASH from steatosis to fibrosis and cirrhosis, inflammation plays an important role because of the activation of Kupffer cells and increased migration of monocytes, dendritic cells, neutrophils, and activated T lymphocytes into the tissues. Macrophages originating from monocytes, with NASH progression, gradually begin to prevail over the pool of resident macrophages. The risk of NASH and fibrosis development in patients with NAFLD increases with the ratio of neutrophils/lymphocytes in the liver. An increase in the Th17 cell count and a decrease in T-regulatory cell count can contribute to increased hepatic steatosis and inflammation development in NAFLD and accelerate the transition from simple steatosis to steatohepatitis and fibrosis. Information on the participation of noncoding RNAs in the regulation of the balance of immune cells in NAFLD is presented, which also allows us to consider them as additional, along with cellular, markers of disease progression.

Cytokine profile in peripheral blood mononuclear cells differs between embryo donor and potential recipient sows.

Pregnancy success relies on the establishment of a delicate immune balance that requires the early activation of a series of local and systemic immune mechanisms. The changes in the immunological profile that are normally occurring in the pregnant uterus does not take place in cyclic (non-pregnant) uterus, a fact that has been widely explored in pigs at the tissue local level. Such differences would be especially important in the context of embryo transfer (ET), where a growing body of literature indicates that immunological differences at the uterine level between donors and recipients may significantly impact embryonic mortality. However, whether components of peripheral immunity also play a role in this context remains unknown. Accordingly, our hypothesis is that the immune status of donor sows differs from potential recipients, not only at the tissue local level but also at the systemic level. These differences could contribute to the high embryonic mortality rates occurring in ET programs. In this study differences in systemic immunity, based on cytokine gene expression profile in peripheral blood mononuclear cells (PBMCs), between embryo-bearing donor (DO group; N = 10) and potential recipient sows (RE group; N = 10) at Day 6 after the onset of the estrus were explored. Gene expression analysis was conducted for 6 proinflammatory (IL-1α, IL-1β, IL-2, GM-CSF, IFN-γ, and TNF-α) and 6 anti-inflammatory (IL-4, IL-6, IL-10, IL-13, TGF-β1, and LIF) cytokines. All cytokines were overexpressed in the DO group except for IL-4, suggesting that stimuli derived from the insemination and/or the resultant embryos modify the systemic immune profile in DO sows compared to RE (lacking these stimuli). Our results also suggest that certain cytokines (e.g., IL-1α and IL-1β) might have a predictive value for the pregnancy status.

Impact of Alcohol on Inflammation, Immunity, Infections, and Extracellular Vesicles in Pathogenesis.

Alcohol consumption is a widespread social activity with a complex and multifaceted impact on human health. Although moderate alcohol consumption has been associated with certain potential health benefits, excessive or chronic alcohol use can disrupt the body's immune balance, promote inflammation, and increase susceptibility to infections. The deleterious effects associated with alcohol toxicity include the loss of cell integrity. When cells lose their integrity, they also lose the capacity to communicate with other systems. One of the systems disturbed by alcohol toxicity is extracellular vesicle (EV)-mediated communication. EVs are critical mediators of cell-to-cell communication. They play a significant role in alcohol-induced pathogenesis, facilitating communication and molecular exchange between cells, thereby potentially contributing to alcohol-related health issues. Investigating their involvement in this context is fundamental to resolving the intricate mechanisms behind the health consequences of alcohol use and may pave the way for innovative approaches for mitigating the adverse effects of alcohol on immune health. Understanding the role of EVs in the context of alcohol-induced pathogenesis is essential for comprehending the mechanisms behind alcohol-related health issues.

Abstract 2684: Pan-cancer neutrophil profiling illuminates anti-tumor antigen-presenting potency

Abstract Neutrophils, the most abundant and efficient defenders against pathogens, exert opposing functions across cancer types. However, given their short half-life and fragile proliferation, it remains challenging to explore how neutrophils adapt to specific fates in cancer. Here we generated and integrated single-cell neutrophil transcriptomes from 17 cancer types (225 samples, 143 patients). Neutrophils exhibited extraordinary complexity, with 10 distinct cell states along differentiation paths including inflammation, angiogenesis, and antigen presentation. Notably, the antigen-presenting program was associated with favorable survival in most cancers and could be evoked by leucine metabolism and subsequent histone H3K27ac modification. These neutrophils could further invoke both (neo)antigen-specific and antigen-independent T-cell responses. Neutrophil delivery or leucine diet fine-tuned the immune balance to boost anti-PD-1 therapy in various murine cancers. In summary, these data not only unravel the neutrophil divergence across cancers, but also offer therapeutic opportunities such as antigen-presenting neutrophil delivery. Citation Format: Ying Cheng Wu, Jiaqiang Ma, Qiang Gao. Pan-cancer neutrophil profiling illuminates anti-tumor antigen-presenting potency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2684.

Blood Transcriptomics Identifies Multiple Gene Expression Pathways Associated with the Clinical Efficacy of Hymenoptera Venom Immunotherapy.

Allergen-specific venom immunotherapy (VIT) is a well-established therapy for Hymenoptera venom allergy (HVA). However, the precise mechanism underlying its clinical effect remains uncertain. Our study aimed to identify the molecular mechanisms associated with VIT efficiency. We prospectively included 19 patients with HVA undergoing VIT (sampled before the beginning of VIT, after reaching the maintenance dose, one year after finishing VIT, and after a sting challenge) and 9 healthy controls. RNA sequencing of whole blood was performed on an Illumina sequencing platform. Longitudinal transcriptomic profiling revealed the importance of the inhibition of the NFκB pathway and the downregulation of DUX4 transcripts for the early protection and induction of tolerance after finishing VIT. Furthermore, successful treatment was associated with inhibiting Th2, Th17, and macrophage alternative signalling pathways in synergy with the inhibition of the PPAR pathway and further silencing of the Th2 response. The immune system became activated when reaching the maintenance dose and was suppressed after finishing VIT. Finally, successful VIT restores the immune system's balance to a state similar to that of healthy individuals. Our results underline the important role of the inhibition of four pathways in the clinical effect of VIT: Th2, Th17, NFκB, and macrophage signalling. Two biomarkers specific for successful VIT, regardless of the time of sampling, were C4BPA and RPS10-NUDT3 and should be further tested as potential biomarkers.

Ilex kudingcha’s phenolic-rich fraction inhibits murine squamous cell carcinoma (SCC7) through restoring adaptive immunity and Th1-polarized immune balance in vitro and in vivo

The Ilex kudingcha methanol extract ethanol supernatent (ESIKME) was analyzed for its phenolic compounds using high-performance liquid chromatography. Murine squamous cell carcinoma (SCC)-7 was treated in vitro and in vivo. ESIKME was found abundant in 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid and modulated the immune response toward Th1-polarized immune balance through changing the splenocytes’ Th1/Th2 cytokine secretion profile in vitro. ESIKME had a significant effect against SCC7 cells in vitro. ESIKME administration by daily gavage for 26 days did not cause any apparent toxicity to SCC7-bearing mice. There were relatively lower tumor weights in the medium dose group (KM, 100 mg/kg b.w./day). KM administration slightly restored the B-cell and T-cell immunity through increasing serum non-specific antibody levels and the splenocytes’ proliferative ability in the experimental mice. KM administration tended to increase Th1-polarized immune balance through increasing (IL-2+TNF-⍺)/IL-10 (Th1/Th2) secretion ratios using splenocytes isolated from the experimental mice. Th1/Th2 cytokine secretion ratios by splenocytes were negatively correlated with tumor weights, revealing that ESIKME inhibits SCC7 through restoring adaptive immunity and Th1-polarized immune balance. Our results are the first to prove that ESIKME, which is a phenolic-rich fraction, inhibits SCC7 through partly restoring adaptive immunity and Th1-polarized immune balance in the tumor-bearing mice.

Synthesis of Pseudostellaria heterophylla polysaccharide-gold nanocomposites and their antitumor effect through immunomodulation.

Polysaccharides from natural sources have an excellent immune function and low toxicity; however, their limitations such as short half-life and instability limit their sustained pharmacological activity. In this context, the combination of polysaccharides and nanotechnology have been developed to promote the stability and prolong the immune activities of polysaccharides. To synthesize and explore the antitumor effect and immunomodulatory activity of PHP-AuNPs. Polysaccharides extracted from Pseudostellaria heterophylla were used to synthesize gold nanocomposites (PHP-AuNPs), and their physicochemical properties and immunoregulatory effect in vitro and in vivo were analyzed. The PHP-AuNPs were green synthesized with high biosafety. PHP-AuNPs can activate macrophages in vitro and decrease the tumor weight and volume, whereas they increase the immune organ index in vivo. Besides, PHP-AuNPs showed a beneficial effect for maintaining the immune balance of CD4+/CD8+ T cells and modulating the release of cytokines such as TNF-α increase and IL-10 decrease in mice. All these results suggested that PHP-AuNPs exhibit a remarkable antitumor effect and stronger immunomodulatory activity than that of free PHP-1. RESEARCH HIGHLIGHTS: The P. heterophylla polysaccharide-gold nanocomposites (PHP-AuNPs) were synthesized and physicochemical properties were characterized. The cytotoxicity in vitro and immunomodulatory effects of PHP-AuNPs on macrophages were analyzed. The immune-antitumor effects in vivo of PHP-AuNPs have also been confirmed.

The Immunomodulatory Potential of Short-Chain Fatty Acids in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative central nervous system (CNS) disorder, characterized by focal inflammation, demyelination, irreversible axonal loss and neurodegeneration. The proposed mechanism involves auto-reactive T lymphocytes crossing the blood-brain barrier (BBB), contributing to inflammation and demyelination. Pro-inflammatory Th1 and Th17 lymphocytes are pivotal in MS pathogenesis, highlighting an imbalanced interaction with regulatory T cells. Dysbiosis in the gut microbiota, characterized by microbial imbalance is implicated in systemic inflammation, yet its exact role in MS remains elusive. Short-chain fatty acids (SCFAs), including valerate, butyrate, propionate, and acetate, produced through dietary fiber fermentation by the gut microbiota, modulate inflammation and immune responses. Particularly, butyrate and propionate exhibit pronounced anti-inflammatory effects in both the gut and CNS. These SCFAs influence regulatory T lymphocyte expression and BBB permeability. This review discusses the potential therapeutic implications of SCFA in MS, highlighting their ability to modulate the gut-brain axis and restore immune balance.

ZDHHC20-driven S-palmitoylation of CD80 is required for its costimulatory function.

CD80 is a transmembrane glycoprotein belonging to the B7 family, which has emerged as a crucial molecule in T cell modulation via the CD28 or CTLA4 axes. CD80-involved regulation of immune balance is a finely tuned process and it is important to elucidate the underlying mechanism for regulating CD80 function. In this study we investigated the post-translational modification of CD80 and its biological relevance. By using a metabolic labeling strategy, we found that CD80 was S-palmitoylated on multiple cysteine residues (Cys261/262/266/271) in both the transmembrane and the cytoplasmic regions. We further identified zDHHC20 as a bona fide palmitoyl-transferase determining the S-palmitoylation level of CD80. We demonstrated that S-palmitoylation protected CD80 protein from ubiquitination degradation, regulating the protein stability, and ensured its accurate plasma membrane localization. The palmitoylation-deficient mutant (4CS) CD80 disrupted these functions, ultimately resulting in the loss of its costimulatory function upon T cell activation. Taken together, our results describe a new post-translational modification of CD80 by S-palmitoylation as a novel mechanism for the regulation of CD80 upon T cell activation.

Interaction between immuno-stem dual lineages in jaw bone formation and injury repair.

The jawbone, a unique structure in the human body, undergoes faster remodeling than other bones due to the presence of stem cells and its distinct immune microenvironment. Long-term exposure of jawbones to an oral environment rich in microbes results in a complex immune balance, as shown by the higher proportion of activated macrophage in the jaw. Stem cells derived from the jawbone have a higher propensity to differentiate into osteoblasts than those derived from other bones. The unique immune microenvironment of the jaw also promotes osteogenic differentiation of jaw stem cells. Here, we summarize the various types of stem cells and immune cells involved in jawbone reconstruction. We describe the mechanism relationship between immune cells and stem cells, including through the production of inflammatory bodies, secretion of cytokines, activation of signaling pathways, etc. In addition, we also comb out cellular interaction of immune cells and stem cells within the jaw under jaw development, homeostasis maintenance and pathological conditions. This review aims to eclucidate the uniqueness of jawbone in the context of stem cell within immune microenvironment, hopefully advancing clinical regeneration of the jawbone.

Synergizing Immune Balance: Curcumin Gold Nanoparticles and Ultrasound Irradiation for Macrophage Down-Regulation

The multifaceted health benefits of curcumin (Curcuma longa), attributed to its antioxidant, antitumor, and anti-inflammatory activities, have drawn significant scientific attention. Curcumin shows promise as a potential modulator of macrophage polarization, offering a natural strategy for managing inflammation and promoting tissue repair. However, a limiting factor for this beneficial molecule is its limited bioavailability due to its low solubility in water. This study aimed to quantify the effect of curcumin gold nanoparticle (CurAuNP)-mediated ultrasound irradiation on THP-1-derived macrophages as potential therapeutic targets. The photoreduction method was applied to synthesize the gold nanoparticles with curcumin as a ligand (CurAu). The effect of adding polyethylene glycol in the synthesis process was studied (CurAuPEG). CurAuNP characterization included UV/Vis, Zeta potential, transmission electron microscopy, and FTIR. The amount of singlet oxygen released by curcumin and CurAuNPs was quantified by observing 1.3-diphenylisobenzofuran quenching upon ultrasound irradiation (1 MHz and 1 W/cm2). The results indicated that ultrasound therapy for 4 min with CurAuNPs significantly enhanced singlet oxygen generation and reduced macrophage viability compared to curcumin alone. The increased sonoluminescence and curcumin delivery facilitated by CurAuNPs led to greater curcumin activation. Consequently, CurAuNPs could offer promising therapeutic options for modulating macrophage polarization in pro-inflammatory and anti-inflammatory stages.